Why shouldn’t MSers engage with drug development for progressive MS? #ResearchSpeak #MSBlog
“The following is a personal email I received from a reader on the blog that I thought I should respond to via the blog as it has relevance to many people with PPMS.”
Problem with sleeping, due to anxiety, so I thought I just drop you a line, that hopefully you can air about in your blog.
I wonder if you can bring up in your blog, the statement you made earlier on in your blog about an experimental agent called laquinimod (LAQ). It was written some time ago, namely 10 sept 2013 and also I managed to google an abstract where you were one of the authors connected to Ectrims 2014.
The title of the blog that you wrote is: “Is laquinimod the new wonder drug that progressive MSers need?“. The statement you made in this blog , was that laquinimod is the first drug that has shown in phase III Clinical trials to have an impact on disability INDEPENDENT of RELAPSES and MRI activity. And to my understanding the HR was 0.61, in essence a 39% risk reduction in relapse free patients to have CDP (confirmed disability progression) in favour for laquinimod.
QUESTION 1: so since I have progressive MS myself, I of course wonder if that statement sticks, to your best knowledge; I mean that laquinimod is the first drug able to halt disability in non-relapsing MS patients in the Phase III studies, even if it was in RRMS patients? If your statements sticks, it sounds inspiring and that I as a patient could be cautiously optimistic about the ongoing PPMS trial with this laquinimod. Who knows, maybe this agent will have a fair chance for success in PPMS. We have now Ocrelizumab, but I was a little disappointed by the results. But the hype was too big, so there were bound to be some disappointments.
REPLY: “Yes, I stick by my statement that laquinimod has a striking impact on disability, and for that matter progressive brain volume loss, or brain atrophy, independently of relapses. It is not necessarily the only drug, when we do so called post-hoc analyses of subjects in other studies of high efficacy drugs we also see an effect when we compare these to placebo-treated subjects who were relapse-free in the studies. However, are these patients really relapse-free? In other words they may have had subclinical relapses (MRI activity) that was driving disease progression. But laquinimod is a DMT that only has a modest effect on relapses and focal MRI activity and yet has a much larger impact on disability progression and brain atrophy. This observation is not unique to laquinimod and has been observed with another drug called ibudilast, which is also in phase 2 clinical trials in progressive MS. It is clear that these drugs are working downstream of focal inflammatory MS lesions and may be targeting the so called hot-microglia that we think are responsible for driving some of the nerve and axonal loss in progressive MS.”
REPLY: “I don’t think you should be disappointed by the results of the ocrelizumab results. They were clearly positive in an early population of people with PPMS. Ocrelizumab may become the platform treatment onto which we add neuroprotective drugs like laquinimod. Who knows the combination of ocrelizumab and laquinimod may be so much more effective than either agent alone.”
QUESTION 2: Furthermore, I also found an abstract, where you contributed, with the title “Ambulation benefit with laquinimod in patients with worsening MS (EDSS over 3) is consistent with reduction in confirmed disability progression“. It was published at Ectrims in October 2014 (see abstract below). Now my second and last last question would be, that apart from that this poster and abstract showed some positive result for the subgroup EDSS over 3, in that the laquinimod subgroup showed a 59% treatment effect on the MSFC measure T25FW, you also made a remark or conclusion, that “an interaction between LAQ treatment effect on T25FW and CDP (I quote abstract) was found: pts on PBO in the EDSS > 3, who also showed CDP declined with 8.6 seconds more than equivalent LAQ treated patients”. This should also work in favour for having some hopes for laquinimod in PPMS. So this measure also works in favour, or points, in a direction that laquinimod could serve a treatment purpose in PPMS in the future, given that ongoing trials will hopefully show positive results. So my question is then: does this abstract, “Ambulation benefit with laquinimod in patients with worsening MS (EDSS over 3) is consistent with reduction in confirmed disability progression “, provide a reasonable rational to perform a PPMS study with laquinimod – especially combined with the positive results on CDP in non-relapsing patients – a penny for your thoughts on the matter Prof Gavin?
REPLY: “Yes, these observations and the effect of laquinimod on brain volume loss is precisely the reason why we are doing a study of laquinimod in PPMS. Teva the sponsor of this study would not be spending large amounts of money unless there was a compelling case for testing laquinimod in PPMS. I should add that there is also a large unmet need in this group as well.”
To be noted: I am aware of that Teva have had to terminate the highest dose, 1.5 mg in PPMS. But the dose 0.6 mg continues, and the above results is, to my best understanding, based on the 0.6 mg dose, which were used in both previously performed phase III studies with laquinimod. To my best understanding, this dose 0.6 had no arising safety problems, as the case were with the dose 1.5 mg.
REPLY: “Yes, you are correct the safety signal that has been noted with with the higher doses of laquinimod. There was a press release earlier this year that stated that non-fatal cardiovascular events occurred in 8 people on the higher doses (1.2mg or 1.5mg).”
Remark, for the record: According to abstract there were no significance different between PASAT and 9HPT z scores. But the MSFC measure T25FW results seem solid enough – yes encouraging; which, to my opinion was rather impressive, if it would stick in the PPMS study Arpeggio with laquinimod.
REPLY: “Yes, I agree with you and that is why we are continue to recruit and follow-up all the patients in the ARPEGGIO, or PPMS laquinimod, study. I am the principal investigator on this study and am very supportive of it continuing, for the reasons you highlight above.”
I have some problems with upper limbs, which negatively affect my ability to write, so please excuse me for all spelling errors and also it is very late into the night. Most obliged if you could give an comment on this agents prospects in PPMS, based on your “claims” or statement before, as aired above.
REPLY: “I remain very optimistic about laquinimod as a potential treatment for PPMS. I still standby my previous posts that I think laquinimod, or a laquinimod-like drugs, will be best used as add-on neuroprotective therapies. According to our treatment pyramid below they will need to be added onto a platform anti-inflammatory therapy. However, to do combination therapy trials you have to have one of the drugs licensed. So the big debate in our heads is which agent should you add laquinimod on to? My preference would be to add on top of an induction therapy.”
Now time to go to bed. And in fact a little less anxiety about my MS disease after this writing. Sometimes it helps just to write on the matter, especially if you see some hope out there.
REPLY: “Thank you for taking the time to read our blog and to make quite sophisticated arguments about how we need to treat PPMS. I actually thrilled to see someone with PPMS have such a clear understanding what we are trying to achieve and more importantly has hope. Hope is such a positive thing; a world without hope would be a very dark place.”
“Don’t worry about your writing, I took the liberty of make a few minor grammatical and typographical corrections to make it easier for the readers. Sleep well.”
Background: In pooled data from the Phase III ALLEGRO and BRAVO studies of oral laquinimod (LAQ) 0.6mg once-daily (QD) vs. placebo (PBO) in RRMS, a 46% reduction in 6-month confirmed disability progression (CDP) was not accompanied by a significant treatment (Tx) effect on the Multiple Sclerosis Functional Composite (MSFC). However, for a subgroup of LAQ-treated patients (pts) with worsening MS (EDSS >3 at baseline [BL]), a 53% reduction in 6month CDP was accompanied by a significant MSFC effect vs. PBO.
Objectives: To investigate LAQ 0.6mg QD Tx effects on individual MSFC components in the pooled ALLEGRO and BRAVO pt subgroup with BL EDSS score >3, and to determine the association between MSFC component scores and improvements in CDP.
Methods: Pooled data from ALLEGRO and BRAVO (N=1990) were used for this post hoc analysis of LAQ vs. PBO Tx effects on change in MSFC subscores at 24 months for the Paced Auditory Serial Addition Test (PASAT), 9-Hole Peg Test (9HPT), and Timed 25-Foot Walk (T25FW), in pts with EDSS >3 at BL. Adjusted mean z-score differences and 95%CIs were evaluated by ANCOVA. CDP was defined as an increase of 1 point if BL EDSS was ≤5.0, or of >0.5 point if BL EDSS was 5.5.
Results: Overall, 655 pts (33%) had a BL EDSS score >3 (LAQ n=328, PBO n=327), with a mean (SD) BL EDSS score of 4.1 (0.7). At BL, pts in the EDSS >3 subgroup were older than pts with BL EDSS ≤3 (mean age 41 vs. 37 years, respectively), had longer disease duration (5.2 vs. 3.7 years), and less brain volume (1547 vs. 1601 cm3). Mean (SD) T25FW time at BL was 8.29 (6.8) seconds (5.40 [5.3] seconds in the EDSS ≤3 subgroup). A 59% LAQ Tx effect on mean [SE] T25FW time (-2.79 [0.96] seconds, 95%CI -4.66, -0.92; p=.0035) appeared to drive the overall MSFC benefit in the EDSS >3 subgroup. There was no significant difference between LAQ and PBO for change in PASAT or 9HPT z-scores, though change directions favored LAQ. Further, an interaction between LAQ Tx effect on T25FW and CDP was found: pts on PBO in the EDSS >3 subgroup who also showed CDP declined by 8.6 seconds more than equivalent LAQ-treated pts.
Conclusions: In pts with worsening MS and EDSS >3 at BL, LAQ was associated with a substantial benefit on ambulatory function as measured by the T25FW, consistent with LAQ CDP benefit in these pts.
CoI: multiple, I am the principal investigator on the PPMS laquinimod trial